Interstitial cystitis (“IC”) is a chronic progressive disorder of the lower urinary tract affecting both men and women marked by an inflammation or irritation of the bladder leading to urinary urgency, frequency and/or tenderness or pain in the bladder and surrounding pelvic area. Recent studies have indicated that up to 80-85% of women of the approximately nine million women who suffer from chronic pelvic pain may have interstitial cystitis (see Parsons et al., “Gynecologic presentation of interstitial cystitis as detected by intravesical potassium sensitivity,” Obstet Gynecol, 98(1):127-132 (2001); Parsons et al., “The prevalence of interstitial cystitis in gynecologic patient with pelvic pain as detected by intravesical potassium sensitivity,” Am J Obstet Gynecol, 187(5):1395-1400 (2002), the contents of both of which are incorporated by reference in their entirety).
Though its etiology is unknown, it is believed that the protective layer of glycosaminoglycans (GAG) that protects the inner epithelial lining of the bladder is somehow disrupted, allowing substances in the urine to irritate the underlying epithelial cells. This disruption in the GAG lining is believed to be caused by an unidentified infection, perhaps of viral origin, that is disrupting the GAG lining or damaging the bladder wall directly, by a substance in the urine that causes the damage, and/or by an autoimmune response following a bladder infection.
Urethral syndrome is a related painful voiding disorder of unknown etiology affecting women exhibiting many similar symptoms set forth above.
Unlike some other diseases of the genitourinary system, such as common cystitis, urethritis, and nephritis, and bacterial prostatitis, IC and urethral syndrome generally do not respond to antibiotic therapy. For most IC patients, and for patients with prostatodynia, a related condition that occurs in men, therapy includes heparinoid therapy with oral pentosan polysulfate (PPS; Elmiron©, Ortho-McNeil/Alza), typically 300-600 mg daily, intravesical heparin (40,000 units in 8 ml of 1% lidocaine and 3 ml sodium bicarbonate once or twice daily), or both. This therapy is usually combined with oral pain medication, antidepressants (to reverse neural activation of bladder nerves that may cause symptoms of pain and urgency to persist even after the epithelium has been restored), and/or antihistamines (to control immune system mast cell degranulation that is believed to provoke IC symptom flares). Heparinoids are similar in structure to the glycosaminoglycans in the bladder surface mucus and are believed to help repair or restore the epithelium in individuals who have abnormal epithelial permeability.
Other therapy options includes bladder instillation wherein the bladder is temporarily filled with a solution containing a therapeutic agent such as dimethyl sulfoxide (DMSO), transcutaneous electrical nerve stimulation (TENS), which delivers mild electric pulses to the bladder area, and as a last resort, bladder surgery.
Despite these treatment options, there is a continuing need for alternative therapies that provide relief from IC symptoms, urethral syndrome and other urological symptoms and/or treat the underlying conditions that trigger these symptoms or prevent them from occurring.
Other leading causes of chronic pelvic pain are uterine fibroids and endometriosis. These two medical conditions affect millions of women in the U.S. and cost billions of dollars in health care dollars each year. Uterine fibroid tumors (also referred to as “uterine fibroids” or “leiomyomas”) are non-cancerous smooth muscle tumors of the uterus. They are believed to occur in 20 percent to 50 percent of women, depending on age and race. Depending on their size and location, fibroids can cause a variety of symptoms, the most common of which are bleeding and “bulk” pelvic pain, and infertility. Some of the most common treatments for fibroids are quite invasive. For example, although a hysterectomy results in the complete removal of the uterus, approximately one-third of the hysterectomies in the United States each year are performed to treat uterine fibroids. Myomectomy is also commonly used to surgically remove uterine fibroids. However, about three-quarters of the myomectomy surgeries are open surgeries involving an abdominal incision. A more recently developed treatment is uterine artery embolization. During this procedure, a catheter is inserted into a femoral artery and guided to a uterine fibroid artery. Small particles are then injected from the catheter into the fibroid artery, blocking its blood supply and causing it to eventually shrink and die. Although this procedure is less invasive than the above procedures, it commonly results in pain-related post-surgical symptoms. Myolysis and cryomyolysis are other techniques in which uterine fibroids are burned or frozen via laproscopic surgery. Like uterine artery embolization, myolysis/cryomyolysis causes fibroids to die and shrink over time.
Endometriosis, although a separate disease, is believed to be often triggered by the same mechanisms that cause fibroids and can also significantly impact a woman's quality of life. Endometriosis is a condition where the endometrium (the lining of the uterus) is found in locations outside the uterus. This misplaced tissue may be found, for example, on the ovaries, outer wall of the uterus, bowel, bladder, utero-sacral ligaments (ligaments that hold the uterus in place) or peritoneum. On rare occasions, they may be found in distant sites such as the lungs or an armpit. As with fibroids, typical treatments include surgery to remove endometrial plaques by mechanical, electrical or laser means, and hysterectomy.
Non-surgical treatment options for both fibroids and endometriosis include oral administration of pain medication and hormonal therapy. For example, in the case of endometriosis, drug therapy includes non-steroidal anti-inflammatory drugs (NSAIDS) and hormonal therapy to interrupt ovarian function and control menstrual bleeding with hormones such as oral contraceptives, progestins, danazol, GnRH agonists, Mifepristone, selective progesterone receptor modulators (SPRMs) or aromatase inhibitors. Similarly, drug therapy for fibroids includes NSAIDS, oral contraceptives, and GnRH agonists.
For a significant fraction of patients, however, drug therapy, on its own, provides insufficient relief from symptoms caused by the fibroids and/or endometriosis and necessitates subsequent treatment with one of the surgical options discussed above. In addition, since the drugs are administered orally (i.e., systemically) and not directly to the fibroids or the endometrial cysts, the doses of drugs, particularly of hormonal drugs, required to disrupt ovarian function, menstrual bleeding, and/or cause fibroid shrinkage are high enough to cause undesirable side effects.
Hence, there is a continuing need for alternative therapies for the treatment of uterine fibroids and endometriosis, which are less invasive, which provide better relief from pelvic pain and discomfort, which preserve the patient's uterus, and which cause fewer side effects.